Huntington disease (HD) is a progressive, fatal, neurodegenerative disease, with movement disorder, psychiatric features, and cognitive decline. The neurodegeneration is regionally heterogeneous with preferential loss of striatal medium spiny neurons, but with significant atrophy in other regions. This leads to the question whether this pattern of regional degeneration is circuit related, reflecting the anatomic connections of the affected neurons, or by contrast is multifocal. To address this question, we will perform statistical shape analysis of basal ganglia and examine white matter structures connecting atrophied regions with affected cortical regions. We hypothesize that there will be heterogeneous atrophy in selected subcortical regions, and that shape analysis may detect some localized changes early, before overall volumes change significantly. We hypothesize that regional globus pallidus atrophy will correlate with specific local basal ganglia connections, but that regional striatal atrophy will not entirely correlate with connections predicted by regional cortical atrophy. We will also perform complementary analysis of white matter structures. Specifically Aim 1 will perform cross- sectional statistical shape analysis (caudate, putamen, thalamus, hippocampus, nucleus accumbens and globus pallidus) in 351 subjects with and without prodromal HD; Aim 2 will perform longitudinal shape analysis on specific subcortical gray matter regions (as listed above) for 351 subjects with scans at 2 time points; and Aim 3 will perform analysis of white matter structures in to determine whether the regions of striatum most affected receive projections from the regions of cortex most affected, and whether the regions of globus pallidus most affected receive projections from the regions of striatum most affected. PUBLIC HEALTH RELEVANCE: Specific sub-regions of atrophy identified in prodromal and early symptomatic Huntington's Disease (HD) will help determine whether neurodegeneration in HD follows a circuit-based pathway connecting brain structures (similar to prion disease, and as hypothesized for Alzheimer's and Parkinson's disease), or is multifocal. These data will be important for planning interventions, which directly target the brain and thus will be directly relevant for HD therapeutics.